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1.
J. coloproctol. (Rio J., Impr.) ; 40(4): 412-420, Oct.-Dec. 2020. tab, graf
Article in English | LILACS | ID: biblio-1143169

ABSTRACT

ABSTRACT Introduction: Colorectal cancer is the third most common cancer worldwide, with about 15% of these tumours related with microsatellite instability, which confers distinct characteristics to these tumours, both clinicopathological and in the response to treatments. In fact, the poor response to chemotherapy in these tumours has led to the investigation for new treatments, with immunotherapy being the most successful one to date. The focus of this review is to assess the response of microsatellite unstable colorectal cancer to PD-1 blockade, and the mechanisms behind that response. Methods: A PubMed research was conducted, resulting in the inclusion of 47 articles in this review. Results: Microsatellite instability results in a high neoantigen load, leading to a highly active immune microenvironment of the tumour, mainly due to T-cells. To counteract this, there is an upregulation of PD-1, acting as a "brake" for immune cells, facilitating tumour growth and metastasis. This upregulation makes these tumours great candidates for treatment with PD-1 blockade, as seen in many clinical trials, where the overall responses and progression free survival rates were higher than those observed in microsatellite stable tumours. Conclusion: With the importance of colorectal cancer with microsatellite instability new treatments are necessary. Therefore, PD-1 blockade is a promising treatment for colorectal cancer with microsatellite instability, with improvement in survival rates and a better prognosis for these patients.


RESUMO Introdução: O câncer colorretal é o terceiro mais comum em todo o mundo, com cerca de 15% desses tumores relacionados com instabilidade dos microssatélites, o que confere características distintas a esses tumores, tanto clínico patológicas quanto na resposta aos tratamentos. De fato, a fraca resposta à quimioterapia nesses tumores levou à investigação de novos tratamentos, sendo a imunoterapia a mais bem sucedida até o momento. O foco desta revisão é avaliar a resposta do câncer colorretal com microssatélites instáveis ao bloqueio do PD-1 e os mecanismos por trás dessa resposta. Métodos: Foi realizada uma pesquisa na base de dados PubMed, resultando na inclusão de 47 artigos nesta revisão. Resultados: A instabilidade de microssatélites resulta em uma alta carga de neoantígenos, levando a um microambiente imunológico altamente ativo do tumor, principalmente devido às células T. Para neutralizar isso, há uma maior expressão do PD-1, atuando como um "freio" para as células imunes, facilitando o crescimento do tumor e suas metástases. Essa expressão faz desses tumores grandes candidatos ao tratamento com bloqueio PD-1, como demonstrado em vários ensaios clínicos, onde as respostas globais e as taxas de sobrevivência livres de progressão foram maiores do que as observadas em tumores com microssatélites estáveis. Conclusão: Com a importância do câncer colorretal com instabilidade de microssatélites, novos tratamentos são necessários. Portanto, o bloqueio do PD-1 é um tratamento promissor para o câncer colorretal com instabilidade de microssatélites, com melhora nas taxas de sobrevivência e melhor prognóstico para esses pacientes.


Subject(s)
Humans , Male , Female , Colorectal Neoplasms/pathology , Programmed Cell Death 1 Receptor/therapeutic use , Immunotherapy/methods , Microsatellite Instability
2.
Rev. medica electron ; 42(5): 2424-2429, sept.-oct. 2020.
Article in Spanish | LILACS, CUMED | ID: biblio-1144746

ABSTRACT

RESUMEN El cáncer es actualmente uno de los problemas de salud más importantes en la mayoría de los países occidentales. En Cuba, el cáncer es la segunda causa de muerte para todos los grupos de edad superada solo por las enfermedades cardiovasculares. En Matanzas, en los últimos años el cáncer ha mostrado una tendencia creciente con datos de incidencia y prevalencia por encima de la media del país. Por tales motivos realizamos este estudio con el objetivo de evaluar el impacto de la inmunoterapia como una alternativa terapéutica que mejora las funciones de supervivencia en pacientes con cáncer avanzado (AU).


SUMMARY Cancer is actually one of the most important health problems in the occidental countries. In Cuba, cancer is the second cause of death in all ages, under heart diseases. In Matanzas, in the last years cancer had showed and ascending growth on incidence and prevalence, over country media. That is wy, we make this study with the objective to evaluate the impact of inmunotherapy as a therapeutic alternative which increase the survival function in patients with advanced cancer (AU).


Subject(s)
Humans , Male , Female , Clinical Trials as Topic/methods , Neoplasms , Chronic Disease/epidemiology , Risk Factors , Cause of Death , Immunotherapy/methods
3.
Rev. chil. pediatr ; 91(2): 232-238, abr. 2020. tab
Article in Spanish | LILACS | ID: biblio-1098896

ABSTRACT

Resumen: Introducción: El desarrollo de aloanticuerpos neutralizantes anti-factor VIII en hemofilia A es la complicación más seria relacionada al tratamiento. La inducción de tolerancia inmune (ITI) o inmunotolerancia es el único tratamiento que erradica inhibidores, permitiendo utilizar nuevamente factor VIII para el tratamiento o profilaxis de eventos hemorrágicos. Objetivo: reportar la experiencia en niños sometidos a inmunotolerancia en la red pública del país. Pacientes y Método: Análisis retrospectivo y descriptivo de 13 niños con Hemofilia A severa e inhibidores persistentes de alto título, que recibieron ITI y seguimiento completo. Se utilizó concentrado de FVIII plasmático en dosis de 70-180 UI/Kg/diarias, definiendo éxito como la negativización del inhibidor y recu peración de la vida media del FVIII. Resultados expresados en media (rango). Resultados: En 13 pacientes se identificó el inhibidor, a una edad de 17,6 meses (2-48), tras 35,2 días (9-112) de exposición a FVIII. Once pacientes (84,6%) recuperaron la vida media del FVIII, tras 49,6 meses (26-70) de tratamiento. En los pacientes que respondieron, el título del inhibidor se negativizó en 7,3 meses (1-20). Conclusiones: En niños con hemofilia A e inhibidores persistentes de alto título, la ITI tiene un elevado éxito. Dado que el tiempo de respuesta es variable, la inmunotolerancia debe ser personalizada.


Abstract: Introduction: The development of anti-factor VIII neutralizing antibodies in hemophilia A is the most severe com plication related to treatment. Immune tolerance induction (ITI) is the only known treatment for eradicating inhibitors. A successful ITI allows using factor VIII (FVIII) again for the treatment or prophylaxis of hemorrhagic events. Objective: To report the experience of pediatric patients who underwent ITI in the country's public health care network. Patients and Method: Retrospective and descriptive analysis of 13 pediatric patients with severe Hemophilia A and high-titer inhibitors persis tence who underwent ITI and complete follow-up. Plasma-derived FVIII concentrate was used at 70 180 IU/kg/day doses. The success of the treatment is defined by achieving a negative titer and a half life recovery of the FVIII. The results were expressed in median (range). Results: In 13 patients, the inhibitor was identified at an average age of 17.6 months, after 35.2 days of exposure to the FVIII. 11 patients (84.6%) recovered the half-life of FVIII after 49.6 months of treatment. In the patients who responded to treatment, the inhibitor titer was negative at 6 months on average. Conclusions: ITI is the treatment of choice for patients with hemophilia A and inhibitors persistence. ITI must be perso nalized since the time response is variable in each patient.


Subject(s)
Humans , Male , Female , Infant , Child, Preschool , Child , Factor VIII/therapeutic use , Hemophilia A/therapy , Immune Tolerance/immunology , Immunotherapy/methods , Isoantibodies/immunology , Factor VIII/immunology , Retrospective Studies , Follow-Up Studies , Treatment Outcome , Hemophilia A/immunology
4.
Article in English | WPRIM | ID: wpr-878349

ABSTRACT

Objective@#To evaluate the safety and effectiveness of a vaccine based on latent membrane protein 2 (LMP2) modified dendritic cells (DCs) that boosts specific responses of cytotoxic T lymphocytes (CTLs) to LMP2 before and after intradermal injection in patients with nasopharyngeal carcinoma (NPC).@*Methods@#DCs were derived from peripheral blood monocytes of patients with NPC. We prepared LMP2-DCs infected by recombinant adenovirus vector expressing LMP2 (rAd-LMP2). NPC patients were immunized with 2 × 10 @*Results@#We demonstrated that DCs derived from monocytes displayed typical DC morphologies; the expression of LMP2 in the LMP2-DCs vaccine was confirmed by immunocytochemical assay. Twenty-nine patients with NPC were enrolled in this clinical trial. The LMP2-DCs vaccine was well tolerated in all of the patients. Boosted responses to LMP2 peptide sub-pools were observed in 18 of the 29 patients with NPC. The follow-up data of 29 immunized patients from April, 2010 to April 2015 indicated a five-year survival rate of 94.4% in responders and 45.5% in non-responders.@*Conclusion@#In this pilot study, we demonstrated that the LMP2-DCs vaccine is safe and effective in patients with NPC. Specific CTLs responses to LMP2 play a certain role in controlling and preventing the recurrence and metastasis of NPC, which warrants further clinical testing.


Subject(s)
Adult , Aged , Cancer Vaccines/therapeutic use , China , Dendritic Cells/immunology , Female , Humans , Immunotherapy/methods , Injections, Intradermal , Male , Middle Aged , Nasopharyngeal Carcinoma/therapy , Nasopharyngeal Neoplasms/therapy , T-Lymphocytes, Cytotoxic/immunology , Viral Matrix Proteins/therapeutic use , Young Adult
5.
An. bras. dermatol ; 94(3): 264-278, May-June 2019. tab, graf
Article in English | LILACS | ID: biblio-1011108

ABSTRACT

Abstract: Pemphigus vulgaris is a chronic autoimmune bullous dermatosis that results from the production of autoantibodies against desmogleins 1 and 3. It is the most frequent and most severe form of pemphigus, occurring universally, usually between 40 and 60 years of age. It usually begins with blisters and erosions on the oral mucosa, followed by lesions on other mucous membranes and flaccid blisters on the skin, which can be disseminated. There is a clinical variant, pemphigus vegetans, which is characterized by the presence of vegetating lesions in the large folds of the skin. Clinical suspicion can be confirmed by cytological examination, histopathological examination, and direct and indirect immunofluorescence tests. The treatment is performed with systemic corticosteroids, and immunosuppressive drugs may be associated, among them azathioprine and mycophenolate mofetil. More severe cases may benefit from corticosteroids in the form of intravenous pulse therapy, and recent studies have shown a beneficial effect of rituximab, an anti-CD20 immunobiological drug. It is a chronic disease with mortality around 10%, and septicemia is the main cause of death. Patients need long-term and multidisciplinary follow-up.


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Pemphigus/diagnosis , Skin/pathology , Autoantibodies/immunology , Surveys and Questionnaires , Pemphigus/classification , Pemphigus/therapy , Pemphigus/epidemiology , Immunoglobulins, Intravenous/therapeutic use , Desmosomes/immunology , Diagnosis, Differential , Immunosuppressive Agents/classification , Immunosuppressive Agents/therapeutic use , Immunotherapy/methods
6.
Medicina (B.Aires) ; 78(5): 336-348, oct. 2018. ilus
Article in Spanish | LILACS | ID: biblio-976122

ABSTRACT

La activación del sistema inmunológico en pacientes con cáncer ha sido un objetivo histórico en el campo de la oncología. En las últimas décadas, nuestro entendimiento de la respuesta inmunológica antitumoral ha promovido el desarrollo de novedosas estrategias terapéuticas dando como resultado un cambio de paradigma en el tratamiento del cáncer. La utilización de agentes bloqueantes de puntos de chequeo del sistema inmunológico como PD-1/PD-L1 y CTLA-4, de agonistas de moléculas co-estimuladoras como CD137 y OX-40 y la transferencia adoptiva de células T antitumorales modificadas genéticamente han generado importantes beneficios clínicos, reflejados en respuestas objetivas y durader as, en enfermos sin tratamientos convencionales disponibles. Sin embargo, un gran número de pacientes no responde a dichas terapias generando resistencia o sufriendo recaídas de la enfermedad debido a la aparición de circuitos inhibitorios o compensatorios. La combinación racional de estrategias terapéuticas permite eliminar mecanismos de resistencia, mientras que la identificación de biomarcadores predictivos facilita la selección de pacientes respondedores a dichos tratamientos. Recientes ensayos clínicos y estudios pre-clínicos permiten vislumbrar un escenario optimista con importantes desafíos en la implementación de estrategias de inmunoterapia en cáncer.


Recent under-standing of the mechanisms that control immune system homeostasis and orchestrate antitumor responses has prompted the development of novel immunotherapeutic modalities. These include antibodies that target immune checkpoints such as PD-1/PD-L1 and CTLA-4, agonistic antibodies of costimulatory molecules such as CD137 and OX-40 and the adoptive transfer of genetically-modified antitumor T cells. However, a large number of patients do not respond to these therapies and develop resistance as a result of activation of compensatory circuits. Rational combination of immunotherapeutic modalities will help overcome resistance and will increase the number of patients who will benefit from these treatments. Moreover, identification of predictive biomarkers will allow selection of patients responding to these treatments. Emerging clinical trials and pre-clinical studies have shown exciting results anticipating new horizons in the design and implementation of cancer immunotherapeutic modalities.


Subject(s)
Humans , Immunotherapy/trends , Neoplasms/therapy , T-Lymphocytes/immunology , Tumor Microenvironment/immunology , CTLA-4 Antigen , Immunotherapy/methods , Antibodies, Monoclonal/immunology , Neoplasms/immunology
7.
Medicina (B.Aires) ; 78(1): 29-32, feb. 2018. tab
Article in English | LILACS | ID: biblio-894543

ABSTRACT

Hepatocellular carcinoma (HCC) is the second cause of cancer-related death in the world and is the main cause of death in cirrhotic patients. Unfortunately, the incidence of HCC has grown significantly in the last decade. Curative treatments such as surgery, liver transplantation or percutaneous ablation can only be applied in less than 30% of cases. The multikinase inhibitor sorafenib is the first line therapy for advanced HCC. Regorafenib is the standard of care for second-line patients. However, novel and more specific potent therapeutic approaches for advanced HCC are still needed. The liver constitutes a unique immunological microenvironment, although anti-tumor immunity seems to be feasible with the use of checkpoint inhibitors such as nivolumab. Efficacy may be further increased by combining checkpoint inhibitors or by applying loco-regional treatments. The success of immune checkpoint blockade has renewed interest in immunotherapy in HCC.


El hepatocarcinoma (HCC) es la segunda causa de muerte relacionada con el cáncer en el mundo y es la principal causa de muerte en pacientes cirróticos. Desafortunadamente, la incidencia de HCC ha crecido significativamente en la última década. Los tratamientos curativos como la cirugía, el trasplante de hígado o la ablación solo pueden aplicarse en menos del 30% de los casos. El sorafenib es el tratamiento de primera línea para el HCC avanzado, mientras que el regorafenib se reserva como segunda línea. Sin embargo, todavía son necesarios nuevos enfoques terapéuticos potentes y más específicos para el HCC avanzado. El hígado constituye un microambiente inmunológico único, aunque la inmunidad antitumoral parece ser factible mediante el uso de inhibidores de punto de control como nivolumab. La eficacia puede aumentarse adicionalmente combinando inhibidores de puntos de control inmunitario o aplicando tratamientos loco-regionales. En este sentido, el éxito del uso de anticuerpos monoclonales, que bloquean el control inmunitario, ha renovado el interés en la inmunoterapia para el HCC.


Subject(s)
Humans , Carcinoma, Hepatocellular/drug therapy , Antineoplastic Agents, Immunological/therapeutic use , Immunotherapy/methods , Liver Neoplasms/drug therapy , Antibodies, Monoclonal/therapeutic use , Phenylurea Compounds/therapeutic use , Pyridines/therapeutic use , Clinical Trials as Topic , Sorafenib/therapeutic use , Nivolumab/therapeutic use
8.
Clinics ; 73(supl.1): e510s, 2018. tab
Article in English | LILACS | ID: biblio-974959

ABSTRACT

Noncolorectal gastrointestinal (GI) malignancies are among the most frequently diagnosed cancers. Despite the undeniable progress in systemic treatments in recent decades, further improvements using cytotoxic chemotherapy seem unlikely. In this setting, recent discoveries regarding the mechanism underlying immune evasion have prompted the study of molecules capable of inducing strong antitumor responses. Thus, according to early data, immunotherapy is a very promising tool for the treatment of patients with GI malignancies. Noncolorectal GI cancers are a major public health problem worldwide. Traditional treatment options, such as chemotherapy, surgery, radiation therapy, monoclonal antibodies and antiangiogenic agents, have been the backbone of treatment for various stages of GI cancers, but overall mortality remains a major problem. Thus, there is a substantial unmet need for new drugs and therapies to further improve the outcomes of treatment for noncolorectal GI malignancies. "Next-generation" immunotherapy is emerging as an effective and promising treatment option in several types of cancers. Therefore, encouraged by this recent success, many clinical trials evaluating the efficacy of immune checkpoint inhibitors and other strategies in treating noncolorectal GI malignancies are ongoing. This review will summarize the current clinical progress of modern immunotherapy in the field of noncolorectal GI tumors.


Subject(s)
Humans , Gastrointestinal Neoplasms/therapy , Immunotherapy/methods , Biomarkers, Tumor/analysis , Clinical Trials as Topic , Antineoplastic Agents, Immunological/therapeutic use
9.
Clinics ; 73(supl.1): e557s, 2018. tab, graf
Article in English | LILACS | ID: biblio-974950

ABSTRACT

Technological developments have allowed improvements in radiotherapy delivery, with higher precision and better sparing of normal tissue. For many years, it has been well known that ionizing radiation has not only local action but also systemic effects by triggering many molecular signaling pathways. There is still a lack of knowledge of this issue. This review focuses on the current literature about the effects of ionizing radiation on the immune system, either suppressing or stimulating the host reactions against the tumor, and the factors that interact with these responses, such as the radiation dose and dose / fraction effects in the tumor microenvironment and vasculature. In addition, some implications of these effects in cancer treatment, mainly in combined strategies, are addressed from the perspective of their interactions with the more advanced technology currently available, such as heavy ion therapy and nanotechnology.


Subject(s)
Humans , Radiation, Ionizing , Radiotherapy/adverse effects , Immune System/radiation effects , Neoplasms/immunology , Neoplasms/radiotherapy , Radiotherapy/trends , Cell Death/radiation effects , Apoptosis/radiation effects , Apoptosis/immunology , Dose-Response Relationship, Radiation , Immunotherapy/methods , Immunotherapy/trends , Necrosis/etiology
10.
Clinics ; 73(supl.1): e479s, 2018. graf
Article in English | LILACS | ID: biblio-952830

ABSTRACT

While cancer immunotherapy has gained much deserved attention in recent years, many areas regarding the optimization of such modalities remain unexplored, including the development of novel approaches and the strategic combination of therapies that target multiple aspects of the cancer-immunity cycle. Our own work involves the use of gene transfer technology to promote cell death and immune stimulation. Such immunogenic cell death, mediated by the combined transfer of the alternate reading frame (p14ARF in humans and p19Arf in mice) and the interferon-β cDNA in our case, was shown to promote an antitumor immune response in mouse models of melanoma and lung carcinoma. With these encouraging results, we are now setting out on the road toward translational and preclinical development of our novel immunotherapeutic approach. Here, we outline the perspectives and challenges that we face, including the use of human tumor and immune cells to verify the response seen in mouse models and the incorporation of clinically relevant models, such as patient-derived xenografts and spontaneous tumors in animals. In addition, we seek to combine our immunotherapeutic approach with other treatments, such as chemotherapy or checkpoint blockade, with the goal of reducing dosage and increasing efficacy. The success of any translational research requires the cooperation of a multidisciplinary team of professionals involved in laboratory and clinical research, a relationship that is fostered at the Cancer Institute of Sao Paulo.


Subject(s)
Humans , Genetic Therapy/methods , Reading Frames/genetics , Interferon-beta/therapeutic use , Gene Transfer Techniques , Immunotherapy/methods , Neoplasms/therapy , Cell Death/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , Tumor Suppressor Protein p14ARF/genetics , Neoplasms/immunology
11.
Clinics ; 73(supl.1): e429s, 2018. graf
Article in English | LILACS | ID: biblio-952824

ABSTRACT

The immunologic landscape of tumors has been continuously unveiled, providing a new look at the interactions between cancer cells and the immune system. Emerging tumor cells are constantly eliminated by the immune system, but some cells establish a long-term equilibrium phase leading to tumor immunoediting and, eventually, evasion. During this process, tumor cells tend to acquire more mutations. Bearing a high mutation burden leads to a greater number of neoantigens with the potential to initiate an immune response. Although many tumors evoke an immune response, tumor clearance by the immune system does not occur due to a suppressive tumor microenvironment. The mechanisms by which tumors achieve the ability to evade immunologic control vary. Understanding these differences is crucial for the improvement and application of new immune-based therapies. Much effort has been placed in developing in silico algorithms to predict tumor immunogenicity and to characterize the microenvironment via high-throughput sequencing and gene expression techniques. Each sequencing source, transcriptomics, and genomics yields a distinct level of data, helping to elucidate the tumor-based immune responses and guiding the fine-tuning of current and upcoming immune-based therapies. In this review, we explore some of the immunological concepts behind the new immunotherapies and the bioinformatic tools to study the immunological aspects of tumors, focusing on neoantigen determination and microenvironment deconvolution. We further discuss the immune-based therapies already in clinical use, those underway for future clinical application, the next steps in immunotherapy, and how the characterization of the tumor immune contexture can impact therapies aiming to promote or unleash immune-based tumor elimination.


Subject(s)
Humans , Immunotherapy/methods , Neoplasms/immunology , Neoplasms/therapy , Genetic Therapy , Cell Transformation, Neoplastic , Combined Modality Therapy , Tumor Escape/immunology , Cancer Vaccines/therapeutic use , Tumor Microenvironment/immunology , Mutation , Antigens, Neoplasm/analysis , Neoplasms/genetics
12.
Einstein (Säo Paulo) ; 16(4): eAO4278, 2018. tab, graf
Article in English | LILACS | ID: biblio-975101

ABSTRACT

ABSTRACT Objective: To investigate the correlation between total lymphocyte and CD3+ T cell counts in peripheral blood in renal transplant patients treated with anti-thymocyte globulin, and discuss related outcomes. Methods: A single-center, retrospective study involving 226 patients submitted to kidney transplant between 2008 and 2013, and treated with anti-thymocyte globulin for induction or treatment of cellular rejection. Doses were adjusted according to CD3+ T cell or total lymphocyte counts in peripheral blood. Results: A total of 664 paired samples were analyzed. The Spearman's correlation coefficient was 0.416 (p<0.001) for all samples combined; the overall Kappa coefficient was 0.267 (p<0.001). Diagnostic parameters estimated based on total lymphocyte counts were also calculated using the number of CD3+ T cells (gold standard), with a cut off of >20 cells/mm3. Conclusion: Total lymphocyte and CD3+ T cell counts in peripheral blood are not equivalent monitoring strategies in anti-thymocyte globulin therapy.


RESUMO Objetivo: Investigar a correlação entre a contagem de linfócitos totais e células T CD3+ no sangue periférico em receptores de transplante renal submetidos a tratamento com globulina antitimocitária, e discutir resultados relacionados. Métodos: Estudo retrospectivo de centro único envolvendo 226 pacientes submetidos a transplante renal entre 2008 e 2013 e tratados com globulina antitimocitária, para fins de indução ou tratamento de rejeição celular. As doses foram ajustadas de acordo com a contagem de células T CD3+ ou linfócitos totais no sangue periférico. Resultados: No total, 664 amostras pareadas foram analisadas. O coeficiente de correlação de Spearman para as amostras em geral foi de 0,416 (p<0,001) e o coeficiente Kappa, de 0,267 (p<0,001). Os parâmetros diagnósticos estimados com base na contagem de linfócitos totais foram recalculados, empregando-se o número de células T CD3+ (padrão-ouro) e adotando-se o ponto de corte >20 células/mm3. Conclusão: A contagem de linfócitos totais no sangue periférico não substitui a contagem de células T CD3+ enquanto estratégia de monitorização da terapia à base de globulina antitimocitária.


Subject(s)
Humans , Male , Female , Adult , Kidney Transplantation , CD3 Complex , Thymocytes/immunology , Transplant Recipients , Graft Rejection/therapy , Isoantibodies/therapeutic use , Antibodies, Monoclonal/therapeutic use , T-Lymphocytes/immunology , Monitoring, Immunologic/instrumentation , Survival Analysis , Retrospective Studies , Lymphocyte Count , Flow Cytometry/methods , Immunotherapy/methods , Middle Aged
13.
Rev. Assoc. Med. Bras. (1992) ; 63(9): 814-823, 2017. tab, graf
Article in English | LILACS | ID: biblio-896397

ABSTRACT

Summary Following decades of relative ostracism, advances in the treatment of melanoma have brought a new reality for patients, physicians and researchers. While antibodies targeting molecules involved in the modulation of the interaction between melanoma and immune cells changed the meaning of the term "cancer immunotherapy," a better characterization of the molecular aberrations involved in melanoma carcinogenesis prompted the development of inhibitors of the mitogen-activated protein kinase pathway (MAPK) that also led to significant improvements both in response rates and survival. As a result, new drugs have been approved for clinical use in the United States and Europe, including the immune-checkpoint blockers ipilmumab, pembrolizumab and nivolumab, the oncolytic herpesvirus talimogene laherparepvec, and the targeted-agents vemurafenib, dabrafenib, cobimetinib and trametinib. In this article, we review the results of studies that brought new approaches to the bedside and discuss how these developments are being incorporated into the care of patients in Brazil.


Resumo Após décadas de ostracismo, os recentes avanços no tratamento do melanoma trouxeram uma nova realidade para pacientes, médicos e pesquisadores. Enquanto anticorpos monoclonais voltados a moléculas envolvidas na modulação da interação entre células do melanoma e do sistema imune consolidaram o uso da "imunoterapia", um melhor conhecimento acerca das aberrações genômicas envolvidas na carcinogênese do melanoma viabilizaram o desenvolvimento de inibidores da via mitogen-activated protein kinase pathway (MAPK), o que também resultou em ganhos significativos em taxas de resposta e sobrevida. Consequentemente, novas modalidades de tratamento foram aprovadas para uso clínico nos Estados Unidos e na Europa, incluindo os bloqueadores de correceptores imunes ipilimumabe, nivolumabe e pembrolizumabe, o herpesvírus oncolítico talimogene laherparepvec (T-VEC), e os agentes-alvo vemurafenibe, dabrafenibe, cobimetinibe e trametinibe. Nesse artigo, revisamos os resultados que trouxeram novas alternativas para a prática clínica e discutimos a incorporação desses avanços ao cuidado de pacientes no Brasil.


Subject(s)
Humans , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Protein Kinase Inhibitors/administration & dosage , Immunotherapy/methods , Melanoma/drug therapy , Antineoplastic Agents/administration & dosage , Proto-Oncogene Proteins B-raf/administration & dosage
14.
An. bras. dermatol ; 92(6): 830-835, Nov.-Dec. 2017.
Article in English | LILACS | ID: biblio-887132

ABSTRACT

Abstract: The stimulation of the immune system, in order to generate an attack against cancer cells, similarly to that which occurs in infectious disease, has long been matter of interest in oncology; however, only limited success has been achieved, with different treatment strategies tested in recent years. The development of new immune checkpoint inhibitors is currently changing this scenario, and immunotherapy is becoming a real choice among traditional cytotoxic treatments to fight cancer. Recent reports have shown efficacy and safety with the use of pembrolizumab, nivolumab, and ipilimumab for the treatment of different neoplasms, especially melanoma. In this article, we propose a review of the mechanisms of action involved in cancer immunology, the response evaluation of immunotherapies, and its toxicity profile, as well as a summary of the main clinical trials that led to the adoption of these new drugs for melanoma treatment.


Subject(s)
Humans , Antineoplastic Agents, Immunological/therapeutic use , Immunotherapy/methods , Melanoma/immunology , Melanoma/drug therapy , Neoplasms/immunology , Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols , Treatment Outcome , Antibodies, Monoclonal, Humanized/therapeutic use , CTLA-4 Antigen/antagonists & inhibitors , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Ipilimumab/therapeutic use , Antibodies, Monoclonal/therapeutic use
15.
Rev. Soc. Cardiol. Estado de Säo Paulo ; 27(4): 266-273, out.-dez. 2017. tab
Article in Portuguese | LILACS | ID: biblio-879434

ABSTRACT

A evolução do tratamento oncológico resultou no desenvolvimento de fármacos altamente eficazes. No entanto, os efeitos colaterais da terapia antitumoral ainda são frequentes e, muitas vezes, limitantes. Entre os efeitos adversos possíveis, a cardiotoxicidade representa um grupo importante de manifestações, com impacto negativo a curto e longo prazo na evolução desses pacientes. Esses eventos podem ocorrer na ausência de fatores de risco de doença cardiovascular e sua evolução ainda não está totalmente esclarecida. Curiosamente, podem ser desencadeadas tanto por terapias sistêmicas convencionais quanto por novas terapias relacionadas com alvos moleculares específicos. As definições de cardiotoxicidade ainda são diversas e não há um consenso universal. Em linhas gerais, pode ser entendida como qualquer alteração da homeostase do sistema cardiovascular induzida pelo tratamento do câncer. O dano cardíaco pode apresentar-se por vasta gama de condições clínicas, como por exemplo, alterações metabólicas, hipertensão arterial sistêmica, síndromes coronarianas agudas, tromboembolismo arterial e venoso, arritmias, entre outros. Muitos destes eventos têm prognóstico pior que muitas neoplasias. Assim, o conhecimento dos efeitos adversos cardíacos do tratamento antineoplásico é de suma importância, e a avaliação cardiovascular do paciente com câncer é fundamental. O intuito desta revisão é apresentar de forma prática as drogas oncológicas com maior potencial cardiotóxico e discutir de forma resumida seus principais efeitos cardiovasculares. Serão discutidas brevemente as definições, os mecanismos de agressão cardíaca e as manifestações clínicas principais, além da evolução e manejo inicial


The evolution of oncological treatment has resulted in the development of highly effective drugs. However, the side effects of antineoplastic therapy are still frequent, and often limiting. Among the possible adverse effects, cardiotoxicity represents an important group of manifestations, with negative impact on the clinical development of these patients in the short and long terms. These events can occur in the absence of risk factors for cardiovascular disease, and their clinical course is still not fully clarified. Interestingly, they can be triggered by both conventional systemic therapies and by new therapies with specific molecular targets. There are several definitions of cardiotoxicity, and there is no universal consensus. In general terms, it can be understood as any modification of cardiovascular system homeostasis induced by cancer treatment. Cardiac damage can present as a wide range of clinical conditions, such as metabolic changes, systemic arterial hypertension, acute coronary syndromes, arterial and venous thromboembolism, and arrhythmias, among others. Many of these events have a worse prognosis than many neoplasms. Thus, the knowledge of the adverse cardiac effects of antineoplastic treatment is of paramount importance, and the cardiovascular evaluation of the cancer patient is essential. The purpose of this review is to offer a practical presentation of oncological drugs with greater cardiotoxic potential, and to summarize its main cardiovascular effects. The definitions, mechanisms of cardiac aggression, and main clinical manifestations will be briefly discussed, as well as the clinical course and initial management


Subject(s)
Humans , Male , Female , Drug Therapy/methods , Cardiotoxicity/complications , Stroke Volume , Cardiovascular Diseases/therapy , Risk Factors , Paclitaxel/therapeutic use , Ventricular Dysfunction , Radiation Exposure/adverse effects , Anthracyclines/therapeutic use , Immunotherapy/methods , Neoplasms/therapy
16.
Int. braz. j. urol ; 43(4): 615-627, July-Aug. 2017. tab, graf
Article in English | LILACS | ID: biblio-892856

ABSTRACT

ABSTRACT Background In order to induce a potent cytotoxic T lymphocyte (CTL) response in dendritic cell (DC)-based immunotherapy for bladder cancer, various tumor antigens can be loaded onto DCs. Objective The aim of this study was to establish a method of immunotherapy for male patients with non-muscle invasive bladder cancer (NMIBC), using bladder cancer-specific CTLs generated in vitro by DCs. Materials and Methods Monocyte-derived DCs from bladder cancer patients were induced to mature in a standard cytokine cocktail (IL-1β, TNF-α, IL-6, and PGE2: standard DCs, sDCs) or anα-type 1-polarized DC (αDC1) cocktail (IL-1β, TNF-α, IFN-α, IFN-γ, and polyinosinic:polycytidylic acid) and loaded with the UVB-irradiated bladder cancer cell line, T24. Antigen-loaded αDC1s were evaluated by morphological and functional assays, and the bladder cancer-specific CTL response was analyzed by cytotoxic assay. Results The αDC1s significantly increased the expression of several molecules pertaining to DC maturation, regardless of whether or not the αDC1s were loaded with tumor antigens, relative to sDCs. The αDC1s demonstrated increased production of interleukin-12 both during maturation and after subsequent stimulation with CD40L that was not significantly affected by loading with tumor antigens as compared to that of sDCs. Bladder cancer-specific CTLs targeting autologous bladder cancer cells were successfully induced by αDC1s loaded with dying T24 cells. Conclusion Autologous αDC1s loaded with an allogeneic bladder cancer cell line resulted in increased bladder cancer-specific CTL responses as compared to that with sDCs, and therefore, may provide a novel source of DC-based vaccines that canbe used in immunotherapy for male patients with NMIBC.


Subject(s)
Humans , Male , Aged , Urinary Bladder Neoplasms/therapy , Dendritic Cells/immunology , T-Lymphocytes, Cytotoxic/immunology , Cytokines/therapeutic use , Immunotherapy/methods , Urinary Bladder Neoplasms/immunology , Cell Differentiation/immunology , Treatment Outcome , Cell Line, Tumor , Immunotherapy/adverse effects , Middle Aged
18.
Int. braz. j. urol ; 42(5): 942-954, Sept.-Oct. 2016. tab, graf
Article in English | LILACS | ID: lil-796874

ABSTRACT

ABSTRACT The present study describes the histopathological and molecular effects of P-MAPA (Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride) intravesical immunotherapy combined with systemic doxorubicin or cisplatin for treatment of non-muscle invasive bladder cancer (NMIBC) in an appropriate animal model. Our results showed an undifferentiated tumor, characterizing a tumor invading mucosa or submucosa of the bladder wall (pT1) and papillary carcinoma in situ (pTa) in the Cancer group. The histopathological changes were similar between the combined treatment with intravesical P-MAPA plus systemic Cisplatin and P-MAPA immunotherapy alone, showing decrease of urothelial neoplastic lesions progression and histopathological recovery in 80% of the animals. The animals treated systemically with cisplatin or doxorubicin singly, showed 100% of malignant lesions in the urinary bladder. Furthemore, the combined treatment with P-MAPA and Doxorubicin showed no decrease of urothelial neoplastic lesions progression and histopathological recovery. Furthermore, Akt, PI3K, NF-kB and VEGF protein levels were significantly lower in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments than other groups. In contrast, PTEN protein levels were significantly higher in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments. Thus, it could be concluded that combination of intravesical P-MAPA immunotherapy and systemic cisplatin in the NMIBC animal model was effective, well tolerated and showed no apparent signs of antagonism between the drugs. In addition, intravesical P-MAPA immunotherapy may be considered as a valuable option for treatment of BCG unresponsive patients that unmet the criteria for early cystectomy.


Subject(s)
Animals , Female , Urinary Bladder Neoplasms/therapy , Carcinoma/therapy , Doxorubicin/therapeutic use , Cisplatin/therapeutic use , Immunotherapy/methods , Membrane Proteins/therapeutic use , Antineoplastic Agents/therapeutic use , Rats, Inbred F344 , Urinary Bladder Neoplasms/pathology , Administration, Intravesical , BCG Vaccine , Carcinoma/pathology , Blotting, Western , Reproducibility of Results , NF-kappa B/analysis , Treatment Outcome , Combined Modality Therapy , Disease Progression , Phosphatidylinositol 3-Kinases/analysis , Models, Animal , Vascular Endothelial Growth Factor A/analysis , PTEN Phosphohydrolase/analysis , Proto-Oncogene Proteins c-akt/analysis
19.
Rev. Assoc. Paul. Cir. Dent ; 70(2): 156-163, abr.-jun. 2016. ilus, tab
Article in Portuguese | LILACS, BBO | ID: lil-797067

ABSTRACT

Este artigo refere-se à uma revisão sobre o carcinoma de células escamosas de cabeça e pescoço (HNSCC), o qual está envolvido em cerca de 90% dos cânceres de cabeça e pescoço,originado do revestimento escamoso da superfície das mucosas do trato aero digestivo superior,incluindo cavidade oral, faringe, laringe e trato sino nasal. Atualmente, o HNSCC apresenta-se como o sexto tipo de câncer mais comum no mundo, sendo que apenas 50% dos pacientes permanecem vivos por 5 anos, após o diagnóstico. Devido à sua distribuição acelerada e alta prevalência, este tipo de câncer tornou-se, nas últimas décadas, uma das principais ameaças para a saúde pública. Seu desenvolvimento e progressão vem ganhando um destaque especial,considerando-se as novas descobertas relacionadas à instabilidade no cerne da genômica e epigenômica, metabolômica, remodelamento celular e fatores de risco associados, principalmente com o envolvimento de infecções virais e, mais recentemente, aos aspectos imunológicos inerentes ao microambiente tumoral (TME), principalmente o perfil celular (fibroblastos associados ao câncer, linfócitos T reguladores, linfócitos e macrófagos com perfil imunossupressorTh2 e M2, respectivamente e neutrófilos associados ao tumor) e o perfil humoral (quimiocinas, citocinas imunossupressoras tais como TGF-B, IL-13, IL-10, proteínas responsáveis pela quebrada matrix extracelular–metaloproteases e fatores que contribuem para o desenvolvimento e progressão tumoral mediados pela angiogênese, tais como EGF e VEGF). Nos próximos anos, a compreensão da imunobiologia do HNSCC será paralelamente acompanhada de importantes avanços na detecção precoce de pacientes de alto risco, baseada na identificação de biomarcadores,na manipulação do sistema imune e na compreensão da farmacogenômica.


This article refers to a review about head and neck squamous cell carcinoma (HNSCC), which involves about 90% of all head and neck cancers, originated from the squamous lining of the upperaero digestive tract, including the oral cavity, pharynx, larynx and sinonasal tract. Currently, it is known as the 6th most common cancer in the world and only 50% of patients will remain alive for5 years post-diagnosis. Due to its accelerated spreading and its high occurrence, this kind of cancerhas become, in the last decades, one of the major threats to public health. Its development and progression has been gaining special attention, considering the new findings associated to the coreinstability of genetic and epigenetic, metabolomics, cellular remodeling and associated risk factors,especially with the involvement of viral infections and, more recently, to the immunological aspects inherent from the tumor microenvironment (TME) particularly cell profiles (fibroblast associated with cancer, regulatory T cells, lymphocytes, and macrophages with immuno suppressive profile Th2and M2, respectively, and neutrophils associated with tumor) and humoral profile (chemokines, immuno suppressive cytokines such as TGF-B, IL-13, IL-10, proteins responsible for the breakdown of extracellular matrix- metallo proteinase and factors that contribute to the development and tumor progression mediated by angiogenesis, such as EGF and VEGF). In the upcoming years, under standing the immunobiology of head and neck squamous cell carcinoma will be accompanied simultaneous ly by important advances in the early detection of high-risk patients, based on the identification of biomarkers,on the manipulation of the immune system and on the understanding of the pharmacogenomics.


Subject(s)
Carcinoma, Squamous Cell/classification , Carcinoma, Squamous Cell/complications , Carcinoma, Squamous Cell/diagnosis , Head and Neck Neoplasms , Immunotherapy/methods , Immunotherapy , Tumor Microenvironment/physiology
20.
Braz. j. med. biol. res ; 49(7): e5263, 2016. graf
Article in English | LILACS | ID: lil-785060

ABSTRACT

B7 homolog 1 (B7-H1) is the most potent immunoinhibitory molecule in the B7 family. In this study, we examined the effects of tumor-associated B7-H1 on T-cell proliferation in lung cancer. The expression of B7-H1 in human adenocarcinoma A549 and mouse Lewis lung carcinoma (LLC) cells were examined by flow cytometry. To assess the in vitro effect of tumor-associated B7-H1 on T-cell proliferation, we isolated T cells from peripheral blood mononuclear cells (PBMCs) of healthy individuals, labeled them with carboxyfluorescein succinimidyl ester, and co-cultured them with A549 cells in the absence or presence of anti-B7-H1 antibody. For in vivo analysis, LLC cells were subcutaneously injected into mice treated or not with anti-B7-H1 antibody. T-cell proliferation in both in vitro and in vivo assays was analyzed by flow cytometry. In vitro, co-culturing T cells with A549 cells significantly inhibited the proliferation of the former compared with the proliferation of T cells alone (P<0.01), and the addition of B7-H1 blocking antibody dramatically reversed the inhibition of T-cell proliferation by A549 cells. Similarly, in mice bearing LLC-derived xenograft tumors, in vivo administration of anti-B7-H1 antibody significantly increased the total number of spleen and tumor T cells compared to levels in control mice that did not receive anti-B7-H1 antibody. Functionally, in vivo administration of anti-B7-H1 antibody markedly reduced tumor growth. Tumor-associated B7-H1 may facilitate immune evasion by inhibiting T-cell proliferation. Targeting of this mechanism offers a promising therapy for cancer immunotherapy.


Subject(s)
Humans , Animals , Mice , Adenocarcinoma/pathology , B7-H1 Antigen/analysis , Cell Proliferation , Lung Neoplasms/pathology , T-Lymphocytes/pathology , A549 Cells , Antibodies, Neoplasm/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , Cells, Cultured , Flow Cytometry , Immunotherapy/methods , Mice, Inbred C57BL , Neoplasms, Experimental , Splenic Neoplasms/pathology , Xenograft Model Antitumor Assays
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